Overview

This report describes the meta-analysis of aggregate data on adverse effects of bisphosphonates.

26 studies are considered, which in total reported 112 distinctly-named adverse events. Among these events, there are 102 distinct events for which there is at least one study comparing incidence of that event between a bisphosphonate treatment group and a no-bisphosphonate control group.

For each of these 102 events, the data were analysed in the same way. The methods, and highlighted results, are given in in this document. Extra details for each of these analyses are reported in Appendix 2.

Events might be grouped into categories corresponding to similar physiological systems (as advised by a clinician REF). Here they are analysed independently, though the results are presented in groups.

Treatment groupings

For each event, there is a different set of trials that reported data on that event, giving a different network of comparisons between treatments. Five alternative models for network meta-analysis are compared, defined by different groupings of treatments. From the finest to the coarsest grouping, these are:

  1. Different doses and delivery methods of different drugs considered as different treatments. The network corresponding to this model is shown as the “full network of comparisons” in Appendix 2.

  2. Different delivery methods considered as different treatments, but different doses of the same drug considered as the same treatment.

  3. Different drugs considered as different treatments, but different doses and delivery methods of the same drug considered as the same treatment.

  4. Nitrogenous bisphosphonates and non-nitrogenous bisphosphonates (just clodronate) considered as different treatments.

  5. All bisphosphonates considered as the same treatment.

Non-bisphosphonate control groups were distinguished as either placebo, observation-only or denosumab.

In two studies, treatment arms are distinguished by the different hormone therapies given. These are modelled in the same way as different doses of the same drug. (In Appendix 2, the arm given a hormone therapy that is not an aromatase inhibitor is labelled “notai”).

Network meta-analysis procedure

A network meta-analysis model was obtained for each event using the following procedure. This procedure aims to find the best-fitting model which uses all potentially-relevant data, which requires a “connected network” of treatments.

  1. If the treatment network is disconnected under the finest model (grouping 1), but becomes connected when placebo and observation-only controls are considered to be the same treatment, then these two control groups are considered to be the same. Otherwise these controls are separated.

  2. Starting with the finest model (grouping 1), the treatments are grouped until the resulting treatment network is connected.

  3. All network meta-analysis models ranging from the finest connected model to the coarsest are fitted.

  4. The optimal model is selected from among those which fitted successfully, using the deviance information criterion (DIC REF), a measure of model fit or predictive ability. The network diagram for the selected model is shown in Appendix 2.

  5. If no network meta-analysis model fitted successfully, then the results for that event are reported from direct-data meta-analysis only. Unsuccessful fits are generally due to sparsity of information.

Technical details of the network meta-analysis models, and the model comparison and checking procedure, are reported in Appendix 1.

For the selected model, a corresponding classical meta-analysis is also performed based on the direct comparisons alone.

Full network graph

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Results

Table 1: events affected most by bisphosphonate treatment

This table lists the events and treatments for which either the direct comparison or the selected network meta-analysis model produced a practically and statistically significant treatment effect, defined as either

  • an odds ratio with a posterior median of 1.5 or greater, or
  • a risk difference (for either healthy or cancer patients) with a posterior median of 0.02 or greater,

which is also “statistically significant” (lower credible limit greater than 1 for odds ratios, or 0 for risk differences).

The odds ratio is the ratio of the odds of the event between the treatment group (as defined in the table) and an “observation only” control group.

The risk difference is the estimated absolute risk for patients given the active treatment, minus a constant baseline risk. These baseline risks are listed in the table below. For cancer patients they are obtained from classical meta-analysis of the direct data from the “observation-only” arms of the bisphosphonate trials. For “healthy” patients they are obtained from the placebo arm of the NCT00083174 study of exemestane v placebo for postmenopausal women at high risk of breast cancer. The risk differences are (currently) only calculated under the network meta-analysis model.

Where there is no baseline risk / risk difference for healthy women, this is because the event was not reported in the NCT00083174 study. If the baseline risk is close to zero, then the risk difference will also be negligible.

Treatment

Direct OR

NMA OR

Baseline risk (cancer)

Risk difference (cancer)

Baseline risk (healthy)

Risk difference (healthy)

Proportion of graded events that are serious

MYALGIA

MYALGIA

Ibandronate

2.04 (1.13, 3.85)

0.03

0.03 (0, 0.09)

0.06 (39/611)

MYALGIA

Pamidronate

2.32 (1.09, 5.21)

0.03

0.04 (0, 0.12)

(0/0)

MYALGIA

Zoledronic_acid

1.52 (1.31, 1.75)

2.36 (1.61, 3.6)

0.03

0.04 (0.02, 0.08)

0.03 (47/1343)

stiffness

Zoledronic_acid_2_IV

2.72 (1.46, 5.06)

2.76 (1.27, 5.83)

0.02

0.03 (0, 0.07)

0 (0/37)

OTHERS

ABDOMINAL PAIN

Bisphosphonate

1.51 (1.13, 2.02)

1.51 (1.1, 2.11)

0.13

0.05 (0.01, 0.11)

0.1 (122/1277)

ARTHRALGIA

Nitrogenous

1.53 (1.29, 1.81)

1.54 (1.28, 1.86)

0.17

0.07 (0.04, 0.1)

0.0000

0 (0, 0)

0.04 (189/5071)

BACK PAIN

Nitrogenous

1.54 (1, 2.37)

1.64 (1.08, 2.69)

0.08

0.05 (0.01, 0.11)

0.1

0.05 (0.01, 0.13)

0.03 (37/1247)

CARDIAC EVENTS

Nitrogenous

2.51 (1.52, 4.17)

2.73 (1.33, 6.31)

0.03

0.04 (0.01, 0.12)

0.0020

0 (0, 0.01)

0.62 (143/231)

CARDIAC EVENTS

Non_nitrogenous

5.22 (0.25, 109.67)

4.35 (1.44, 13.6)

0.03

0.08 (0.01, 0.25)

0.0020

0.01 (0, 0.02)

0.32 (21/65)

CHILLS

Zoledronic_acid_IV

8.55 (2.26, 32.32)

15.19 (3.96, 94.86)

0.02

0.24 (0.06, 0.66)

0.01 (3/213)

DIARRHOEA

Non_nitrogenous

3.34 (1.18, 9.45)

1.81 (1.35, 2.74)

0.11

0.07 (0.03, 0.14)

0.03

0.03 (0.01, 0.05)

0.08 (49/591)

DYSGEUSIA

Zoledronic_acid_2_IV

10.1 (1.17, 87.24)

8.53 (1.25, 119.84)

0.0010

0.01 (0, 0.11)

FATIGUE

Bisphosphonate

1.13 (1.02, 1.26)

1.28 (1.06, 1.65)

0.1

0.03 (0.01, 0.06)

0.21

0.04 (0.01, 0.09)

0.05 (247/4607)

FEVER

Pamidronate_IV

1.52 (0.47, 4.92)

4.87 (1.9, 12.62)

0.01

0.05 (0.01, 0.13)

1 (3/3)

FEVER

Zoledronic_acid_IV

4.06 (3.06, 5.38)

5.2 (2.88, 8.79)

0.01

0.05 (0.02, 0.09)

0.09 (82/933)

HEADACHE

Zoledronic_acid

1.19 (1.02, 1.4)

1.48 (1.06, 2.25)

0.24

0.08 (0.01, 0.18)

0.03 (36/1304)

HEPATOTOXICITY

Clodronate_Oral

1.69 (1.05, 2.71)

1.46 (0.78, 2.59)

0.26

0.08 (-0.04, 0.22)

0.15 (14/95)

HEPATOTOXICITY

Ibandronate_Oral

4.27 (1.28, 14.22)

3.39 (1.13, 11.73)

0.26

0.28 (0.02, 0.54)

(0/0)

hypertonia/muscle spasms

Bisphosphonate

1.53 (1.02, 2.3)

1.52 (0.93, 2.81)

0.04

0.02 (0, 0.07)

0.14 (15/106)

HYPOCALCEMIA

Ibandronate

6.15 (1.16, 41.76)

0.04

0.17 (0.01, 0.6)

0.02 (5/210)

HYPOCALCEMIA

Pamidronate

3.23 (1.45, 7.22)

3.18 (1.2, 8.64)

0.04

0.08 (0.01, 0.23)

(0/0)

HYPOCALCEMIA

Zoledronic_acid

7.07 (0.87, 57.56)

7.28 (1.36, 48.93)

0.04

0.2 (0.01, 0.64)

0.03 (11/336)

increased bone pain

Bisphosphonate

1.73 (1.47, 2.04)

1.79 (1.33, 2.49)

0.11

0.07 (0.03, 0.13)

0.1 (352/3386)

INFECTION

Ibandronate_Oral

2.24 (1.18, 4.22)

0.22

0.0009

(0/0)

Influenza-like symptoms

Bisphosphonate

22.18 (2.98, 164.89)

16.09 (2.04, 207.85)

0.03

0.33 (0.03, 0.85)

0.05 (35/718)

NAUSEA

Bisphosphonate

1.21 (1.08, 1.35)

1.33 (1.11, 1.63)

0.34

0.07 (0.02, 0.12)

0.05

0.02 (0.01, 0.03)

0.09 (323/3579)

NEUROSENSORY PROBLEMS

Bisphosphonate

1.23 (1.05, 1.45)

1.29 (1.05, 1.66)

0.1

0.03 (0, 0.06)

0.0000

0 (0, 0)

0.03 (52/1509)

OsteoNecrosis of the Jaw

Nitrogenous

7.69 (2.31, 25.55)

0.0050

(0/0)

periodontal disease

Zoledronic_acid_2_IV

15.34 (0.87, 269.36)

10.2 (1.14, 1322.28)

0.14 (1/7)

THROMBOEMBOLIC EVENTS

Clodronate

7.27 (1.41, 33.44)

0.02

0.11 (0.01, 0.38)

0.0009

0.01 (0, 0.03)

1 (27/27)

THROMBOEMBOLIC EVENTS

Ibandronate

13.15 (2.36, 68.93)

0.02

0.19 (0.03, 0.56)

0.0009

0.01 (0, 0.06)

0.91 (10/11)

THROMBOEMBOLIC EVENTS

Zoledronic_acid

3.18 (1.34, 7.51)

2.79 (0.99, 7.42)

0.02

0.03 (0, 0.11)

0.0009

0 (0, 0.01)

0.72 (28/39)

VOMITING

Non_nitrogenous

1.67 (1.18, 2.92)

0.19

0.09 (0.03, 0.22)

0.0004

0 (0, 0)

0.03 (9/312)

Note the reported “treatment” in these tables depends on the selected model - this could refer to all bisphosphonates, or the dose and delivery method of a particular drug, or some categorisation in between. If the selected model distinguishes between doses, the dose categories are labelled with a number.

Events that are significant if we just include studies with complete reporting.

The same procedure above was followed to select an optimal network meta-analysis model for the data including just studies with “complete” reporting. About half of the events selected above still have significant treatment effects, though perhaps for a slightly different treatment definition. Many are no longer “significant”, and there are some new ones (hypertonia/muscle spasms, dysgeusia, abdominal pain) that become “significant” by some criterion.

Treatment

Direct OR

NMA OR

Baseline risk (cancer)

Risk difference (cancer)

Baseline risk (healthy)

Risk difference (healthy)

Proportion of events that are serious

MYALGIA

MYALGIA

Zoledronic_acid

3.3 (2.06, 5.28)

3.22 (1.65, 5.83)

0.03

0.07 (0.02, 0.14)

0.03 (28/1034)

OTHERS

BACK PAIN

Nitrogenous

2.19 (0.78, 6.13)

2.46 (1, 6.6)

0.08

0.1 (0, 0.29)

0.1

0.11 (0, 0.32)

0.03 (37/1243)

CARDIAC EVENTS

Clodronate_1_Oral

5.22 (0.25, 109.67)

7.84 (1.27, 33.46)

0.03

0.15 (0.01, 0.45)

0.0020

0.01 (0, 0.05)

0.32 (21/65)

CARDIAC EVENTS

Ibandronate_3_Oral

12.18 (2.01, 59.73)

0.03

0.22 (0.03, 0.6)

0.0020

0.02 (0, 0.09)

1 (18/18)

DIARRHOEA

Non_nitrogenous

3.34 (1.18, 9.45)

2.91 (1.48, 5.94)

0.11

0.15 (0.04, 0.31)

0.03

0.06 (0.02, 0.14)

0.08 (42/503)

DYSGEUSIA

Bisphosphonate

7.04 (1.2, 41.3)

6.26 (0.95, 74.5)

0.0010

0.01 (0, 0.07)

FATIGUE

Zoledronic_acid_1_IV

1.94 (1.32, 2.84)

1.9 (0.96, 3.94)

0.1

0.08 (0, 0.21)

0.21

0.12 (-0.01, 0.3)

0.01 (19/1335)

FATIGUE

Zoledronic_acid_2_IV

1.76 (1.14, 2.73)

2.38 (1.22, 5.15)

0.1

0.11 (0.02, 0.27)

0.21

0.18 (0.04, 0.37)

0 (0/362)

FEVER

Clodronate_1_Oral

6.54 (1.84, 45.74)

0.01

0.06 (0.01, 0.36)

0.01 (1/83)

FEVER

Ibandronate_3_Oral

8.83 (2.48, 60.44)

0.01

0.09 (0.02, 0.42)

0 (0/70)

FEVER

Zoledronic_acid_1_IV

17.55 (4.24, 72.7)

27.03 (10.19, 179.58)

0.01

0.25 (0.1, 0.69)

0.05 (28/570)

FEVER

Zoledronic_acid_2_IV

34.76 (8.48, 142.55)

30.72 (11.84, 178.43)

0.01

0.27 (0.12, 0.68)

0.03 (6/192)

FEVER

Zoledronic_acid_4_IV

6.8 (2.23, 38.99)

0.01

0.07 (0.02, 0.32)

0.08 (3/37)

HEADACHE

Zoledronic_acid_IV

2.19 (1.36, 3.52)

2.29 (1.32, 3.93)

0.24

0.18 (0.05, 0.31)

0.02 (22/931)

hypertonia/muscle spasms

Bisphosphonate

3.68 (1.12, 12.05)

3.57 (0.94, 22.24)

0.04

0.1 (0, 0.46)

0.21 (12/58)

HYPOCALCEMIA

Bisphosphonate

1.6 (1.03, 2.51)

1.5 (0.76, 2.81)

0.04

0.02 (-0.01, 0.07)

0.02 (9/502)

increased bone pain

Bisphosphonate

1.84 (1.37, 2.48)

1.86 (1.15, 3.08)

0.11

0.08 (0.02, 0.17)

0.07 (147/2131)

NEUROSENSORY PROBLEMS

Bisphosphonate

1.56 (1.1, 2.21)

1.49 (1, 2.23)

0.1

0.04 (0, 0.1)

0.0000

0 (0, 0)

0.02 (23/1429)

NEUTROPENIA

Nitrogenous

2.04 (0.7, 5.93)

2.33 (1, 5.43)

0.04

0.05 (0, 0.15)

0.05 (8/166)

SKIN DISORDER

Bisphosphonate

1.6 (1.03, 2.48)

1.48 (0.87, 2.44)

0.05

0.02 (-0.01, 0.06)

0.03 (37/1142)

THROMBOEMBOLIC EVENTS

Ibandronate

33.15 (1.62, 474.44)

0.02

0.38 (0.01, 0.88)

0.0009

0.03 (0, 0.3)

1 (10/10)

THROMBOEMBOLIC EVENTS

Zoledronic_acid

7.97 (1.4, 45.55)

4.38 (0.53, 46.06)

0.02

0.06 (-0.01, 0.46)

0.0009

0 (0, 0.04)

0.67 (18/27)

Change in results when excluding incomplete reporting

The graph below shows all the events for which

  • a significant odds ratio was highlighted in the main analysis.

  • no significant odds ratio was detected when studies with incomplete reporting were excluded

The treatment categorisations are shown under the best fitting model in the main analysis. Comparing the red and blue lines shows how the results change when studies with incomplete reporting are excluded.

Table 2: Summary of results for every event

Table 2 gives odds ratios from direct and selected network meta-analysis models for all events, sorted by clinical category, including non-significant results. Effects significant by either criterion, as listed in Table 1, are shown here in red.

More detailed results, for all 103 events, including network diagrams, raw data and “forest plots” of meta-analysis results, are given in Appendix 2.

Treatment

Direct OR

NMA OR

Baseline risk (cancer)

Risk difference (cancer)

Baseline risk (healthy)

Risk difference (healthy)

MYALGIA

MYALGIA

Clodronate

1.24 (0.59, 2.6)

0.03

0.01 (-0.01, 0.05)

MYALGIA

Ibandronate

2.04 (1.13, 3.85)

0.03

0.03 (0, 0.09)

MYALGIA

Pamidronate

2.32 (1.09, 5.21)

0.03

0.04 (0, 0.12)

MYALGIA

Zoledronic_acid

1.52 (1.31, 1.75)

2.36 (1.61, 3.6)

0.03

0.04 (0.02, 0.08)

stiffness

Zoledronic_acid_2_IV

2.72 (1.46, 5.06)

2.76 (1.27, 5.83)

0.02

0.03 (0, 0.07)

stiffness

Zoledronic_acid_2notai_IV

1.28 (0.58, 2.85)

1.2 (0.47, 3.09)

0.02

0 (-0.01, 0.03)

OTHERS

ABDOMINAL PAIN

Bisphosphonate

1.51 (1.13, 2.02)

1.51 (1.1, 2.11)

0.13

0.05 (0.01, 0.11)

ALANINE AMINOTRANSFERASE

Clodronate_1_Oral

0.15 (0.02, 3.1)

0.0090

-0.01 (-0.01, 0.02)

0.0004

0 (0, 0)

ALANINE AMINOTRANSFERASE

Ibandronate_3_Oral

0.05 (0.01, 1.15)

0.0090

-0.01 (-0.01, 0)

0.0004

0 (0, 0)

ALANINE AMINOTRANSFERASE

Ibandronate_4_IVAndOral

0.05 (0, 2.34)

0.0090

-0.01 (-0.01, 0.01)

0.0004

0 (0, 0)

ALANINE AMINOTRANSFERASE

Zoledronic_acid_1_IV

0.34 (0.01, 8.33)

0.07 (0.01, 1.38)

0.0090

-0.01 (-0.01, 0)

0.0004

0 (0, 0)

ALANINE AMINOTRANSFERASE

Zoledronic_acid_2_IV

0.08 (0.01, 1.98)

0.0090

-0.01 (-0.01, 0.01)

0.0004

0 (0, 0)

ALKALINE PHOSPHATASE

Zoledronic_acid_1_IV

0.45 (0.09, 2.22)

0.15

0.0000

ALKALINE PHOSPHATASE

Zoledronic_acid_2_IV

0.26 (0.05, 1.33)

0.15

0.0000

ALLERGIC REACTIONS

Zoledronic_acid

3.27 (0.13, 83.03)

0.29 (0.01, 24.71)

0.0000

0 (0, 0)

ALOPECIA

Bisphosphonate

1.05 (0.92, 1.21)

1.11 (0.87, 1.55)

0.06

0.01 (-0.01, 0.03)

ANAEMIA

Nitrogenous

1.16 (0.5, 2.68)

1.13 (0.61, 2.17)

0.01

0 (0, 0.01)

ANAEMIA

Non_nitrogenous

1.01 (0.43, 2.39)

0.96 (0.5, 1.82)

0.01

0 (-0.01, 0.01)

ARTHRALGIA

Nitrogenous

1.53 (1.29, 1.81)

1.54 (1.28, 1.86)

0.17

0.07 (0.04, 0.1)

0.0000

0 (0, 0)

ARTHRALGIA

Non_nitrogenous

1.2 (0.93, 1.58)

0.17

0.03 (-0.01, 0.07)

0.0000

0 (0, 0)

arthropathy/arthritis

Bisphosphonate

1.23 (0.88, 1.72)

1.17 (0.79, 1.69)

0.11

0.02 (-0.02, 0.06)

0.09

0.01 (-0.02, 0.05)

ASPARTATE AMINOTRANSFERASE

Nitrogenous

0.32 (0.1, 1.01)

0.52 (0.2, 1.44)

0.02

-0.01 (-0.01, 0.01)

0.0004

0 (0, 0)

ASPARTATE AMINOTRANSFERASE

Non_nitrogenous

1.44 (0.55, 3.8)

1.2 (0.42, 3.18)

0.02

0 (-0.01, 0.04)

0.0004

0 (0, 0)

ASTHENIA

Nitrogenous

2.53 (0.49, 13.13)

2 (0.43, 8.3)

0.08

0.07 (-0.04, 0.33)

BACK PAIN

Nitrogenous

1.54 (1, 2.37)

1.64 (1.08, 2.69)

0.08

0.05 (0.01, 0.11)

0.1

0.05 (0.01, 0.13)

BACK PAIN

Non_nitrogenous

1.31 (0.79, 2.36)

0.08

0.02 (-0.02, 0.09)

0.1

0.03 (-0.02, 0.11)

BILIRUBIN

Bisphosphonate

0.15 (0.03, 0.83)

0.07 (0.01, 0.58)

0.08

-0.07 (-0.08, -0.03)

CARDIAC: CONGESTIVE HEART FAILURE

Zoledronic_acid_IV

0.2 (0.01, 5.17)

0.05 (0.01, 1.71)

0.04

-0.03 (-0.04, 0.02)

CARDIAC EVENTS

Nitrogenous

2.51 (1.52, 4.17)

2.73 (1.33, 6.31)

0.03

0.04 (0.01, 0.12)

0.0020

0 (0, 0.01)

CARDIAC EVENTS

Non_nitrogenous

5.22 (0.25, 109.67)

4.35 (1.44, 13.6)

0.03

0.08 (0.01, 0.25)

0.0020

0.01 (0, 0.02)

CATARACT

Bisphosphonate

0.84 (0.26, 2.75)

0.44 (0.03, 1.8)

0.0040

0 (0, 0)

CELLULITIS

Bisphosphonate

0.21 (0.01, 5.28)

0.02 (0, 0.64)

0.04

-0.04 (-0.04, -0.01)

CHEST PAIN

Bisphosphonate

4.71 (0.22, 101.87)

0.56 (0.04, 12.08)

0.01

-0.01 (-0.01, 0.12)

CHILLS

Clodronate_Oral

3.45 (0.73, 25.67)

0.02

0.05 (-0.01, 0.35)

CHILLS

Ibandronate_Oral

3.28 (0.72, 24.2)

0.02

0.05 (-0.01, 0.33)

CHILLS

Zoledronic_acid_IV

8.55 (2.26, 32.32)

15.19 (3.96, 94.86)

0.02

0.24 (0.06, 0.66)

COLITIS

Nitrogenous

0.02 (0, 1)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

COLITIS

Non_nitrogenous

1.01 (0.06, 16.11)

0.4 (0.01, 5.82)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

constipation

Bisphosphonate

1.06 (0.93, 1.21)

1.03 (0.82, 1.26)

0.42

0.01 (-0.05, 0.06)

COUGH

Bisphosphonate

1.99 (0.96, 4.13)

1.81 (0.96, 3.63)

0.02

0.01 (0, 0.04)

0.12

0.08 (0, 0.21)

CPK increased

Clodronate_1_Oral

5.04 (0.24, 105.07)

5.48 (0.05, 3472.85)

0.0003

0 (0, 0.52)

DECREASED APPETITE

Nitrogenous

0.98 (0.58, 1.67)

0.89 (0.45, 1.92)

0.04

0 (-0.02, 0.03)

DEHYDRATION

Bisphosphonate

1.18 (0.44, 3.15)

0.91 (0.26, 3.27)

0.0080

0 (-0.01, 0.02)

DEPRESSION

Bisphosphonate

0.96 (0.76, 1.2)

0.96 (0.72, 1.32)

0.02

0 (0, 0.01)

0.1

0 (-0.03, 0.03)

DIARRHOEA

Nitrogenous

0.99 (0.84, 1.16)

1.1 (0.88, 1.55)

0.11

0.01 (-0.01, 0.05)

0.03

0 (0, 0.02)

DIARRHOEA

Non_nitrogenous

3.34 (1.18, 9.45)

1.81 (1.35, 2.74)

0.11

0.07 (0.03, 0.14)

0.03

0.03 (0.01, 0.05)

DIZZINESS

Bisphosphonate

1.44 (0.89, 2.32)

1.33 (0.74, 2.4)

0.03

0.01 (-0.01, 0.04)

0.09

0.03 (-0.02, 0.1)

dry mouth

Bisphosphonate

0.55 (0.2, 1.52)

0.4 (0.12, 1.16)

0.04

-0.02 (-0.04, 0.01)

DYSGEUSIA

Clodronate_1_Oral

3.02 (0.12, 74.25)

1.53 (0.02, 566.04)

0.0010

0 (0, 0.37)

DYSGEUSIA

Ibandronate_3_Oral

1.06 (0.35, 4.52)

0.0010

0 (0, 0)

DYSGEUSIA

Zoledronic_acid_1_IV

1.07 (0.85, 1.35)

1.09 (0.46, 2.86)

0.0010

0 (0, 0)

DYSGEUSIA

Zoledronic_acid_2_IV

10.1 (1.17, 87.24)

8.53 (1.25, 119.84)

0.0010

0.01 (0, 0.11)

DYSPEPSIA

Clodronate

0.44 (0.06, 3.28)

0.04

-0.02 (-0.04, 0.08)

DYSPEPSIA

Ibandronate

0.47 (0.06, 3.59)

0.04

-0.02 (-0.04, 0.09)

DYSPEPSIA

Risedronate

0.29 (0.03, 2.72)

0.04

-0.03 (-0.04, 0.06)

DYSPEPSIA

Zoledronic_acid

0.48 (0.04, 5.46)

0.2 (0.03, 1.51)

0.04

-0.03 (-0.04, 0.02)

dysphagia

Bisphosphonate

0.5 (0.11, 2.3)

0.28 (0.04, 2.64)

0.08

-0.05 (-0.07, 0.1)

0.0000

0 (0, 0)

DYSPNOEA

Nitrogenous

1.47 (0.7, 3.11)

1.34 (0.58, 3.19)

0.02

0.01 (-0.01, 0.04)

0.0004

0 (0, 0)

DYSPNOEA

Non_nitrogenous

0.94 (0.38, 2.33)

0.02

0 (-0.01, 0.03)

0.0004

0 (0, 0)

Elevated creatinine

Clodronate_Oral

1.24 (0.18, 6.04)

0.08

0.02 (-0.07, 0.27)

Elevated creatinine

Ibandronate_IV

0.86 (0.05, 9.43)

0.08

-0.01 (-0.08, 0.38)

Elevated creatinine

Ibandronate_Oral

0.78 (0.07, 4.88)

0.08

-0.02 (-0.08, 0.23)

Elevated creatinine

Pamidronate_IV

0.93 (0.33, 2.64)

0.64 (0.13, 2.39)

0.08

-0.03 (-0.07, 0.1)

Elevated creatinine

Zoledronic_acid_IV

1.15 (0.16, 8.36)

0.74 (0.09, 2.63)

0.08

-0.02 (-0.08, 0.11)

endometrial hyperplasia

Zoledronic_acid_IV

1.12 (0.74, 1.72)

FATIGUE

Bisphosphonate

1.13 (1.02, 1.26)

1.28 (1.06, 1.65)

0.1

0.03 (0.01, 0.06)

0.21

0.04 (0.01, 0.09)

FEBRILE NEUTROPENIA

Clodronate

1.07 (0.05, 8.39)

0.0040

0 (0, 0.03)

FEBRILE NEUTROPENIA

Ibandronate

4.56 (0.36, 39.36)

0.0040

0.02 (0, 0.14)

FEBRILE NEUTROPENIA

Zoledronic_acid

0.98 (0.79, 1.23)

0.85 (0.18, 1.28)

0.0040

0 (0, 0)

FEVER

Clodronate_Oral

0.64 (0.16, 2.36)

0.01

0 (-0.01, 0.02)

FEVER

Ibandronate_IV

2.56 (0.44, 13.76)

0.01

0.02 (-0.01, 0.14)

FEVER

Ibandronate_Oral

0.49 (0.09, 2.03)

0.01

-0.01 (-0.01, 0.01)

FEVER

Pamidronate_IV

1.52 (0.47, 4.92)

4.87 (1.9, 12.62)

0.01

0.05 (0.01, 0.13)

FEVER

Zoledronic_acid_IV

4.06 (3.06, 5.38)

5.2 (2.88, 8.79)

0.01

0.05 (0.02, 0.09)

GGT increased

Non_nitrogenous

5.04 (0.24, 105.07)

4.89 (0.14, 9458.49)

0.0003

0 (0, 0.74)

HAND-FOOT SYNDROME

Clodronate_1_Oral

3.02 (0.12, 74.25)

0.0080

HAND-FOOT SYNDROME

Zoledronic_acid_1_IV

0.91 (0.05, 17.05)

0.0080

HAND-FOOT SYNDROME

Zoledronic_acid_2_IV

2.08 (0.12, 36.73)

0.0080

HEADACHE

Clodronate

0.96 (0.45, 1.78)

0.24

-0.01 (-0.12, 0.12)

HEADACHE

Ibandronate

1.08 (0.59, 1.86)

0.24

0.01 (-0.08, 0.13)

HEADACHE

Pamidronate

1.77 (0.86, 4.09)

0.24

0.12 (-0.03, 0.32)

HEADACHE

Risedronate

0.91 (0.3, 2.76)

0.24

-0.02 (-0.15, 0.23)

HEADACHE

Zoledronic_acid

1.19 (1.02, 1.4)

1.48 (1.06, 2.25)

0.24

0.08 (0.01, 0.18)

HEPATOTOXICITY

Clodronate_Oral

1.69 (1.05, 2.71)

1.46 (0.78, 2.59)

0.26

0.08 (-0.04, 0.22)

HEPATOTOXICITY

Ibandronate_Oral

4.27 (1.28, 14.22)

3.39 (1.13, 11.73)

0.26

0.28 (0.02, 0.54)

HEPATOTOXICITY

Zoledronic_acid_IV

1.08 (0.6, 1.95)

1.2 (0.65, 2.28)

0.26

0.04 (-0.07, 0.19)

HOT FLUSHES

Bisphosphonate

0.95 (0.82, 1.1)

0.93 (0.78, 1.1)

0.24

-0.01 (-0.04, 0.02)

0.32

-0.02 (-0.05, 0.02)

HYPERGLYCAEMIA

Clodronate_1_Oral

0.62 (0.26, 1.49)

0.61 (0.18, 1.7)

0.0100

0 (-0.01, 0.01)

HYPERGLYCAEMIA

Ibandronate_3_Oral

0.55 (0.1, 1.79)

0.0100

0 (-0.01, 0.01)

HYPERGLYCAEMIA

Zoledronic_acid_1_IV

0.68 (0.11, 2.11)

0.0100

0 (-0.01, 0.01)

HYPERGLYCAEMIA

Zoledronic_acid_2_IV

2.55 (0.99, 6.61)

2.51 (0.68, 9.11)

0.0100

0.01 (0, 0.07)

HYPERTENSION

Nitrogenous

1.04 (0.36, 3.04)

0.97 (0.38, 2.59)

0.02

0 (-0.01, 0.03)

0.16

0 (-0.09, 0.17)

HYPERTENSION

Non_nitrogenous

1.31 (0.49, 3.61)

0.02

0.01 (-0.01, 0.04)

0.16

0.04 (-0.07, 0.25)

hypertonia/muscle spasms

Bisphosphonate

1.53 (1.02, 2.3)

1.52 (0.93, 2.81)

0.04

0.02 (0, 0.07)

hypoalbuminemia

Bisphosphonate

5.04 (0.24, 105.07)

3.28 (0.05, 301.58)

0.0003

0 (0, 0.08)

HYPOCALCEMIA

Clodronate

5.56 (0.94, 37.94)

0.04

0.15 (0, 0.58)

HYPOCALCEMIA

Ibandronate

6.15 (1.16, 41.76)

0.04

0.17 (0.01, 0.6)

HYPOCALCEMIA

Pamidronate

3.23 (1.45, 7.22)

3.18 (1.2, 8.64)

0.04

0.08 (0.01, 0.23)

HYPOCALCEMIA

Zoledronic_acid

7.07 (0.87, 57.56)

7.28 (1.36, 48.93)

0.04

0.2 (0.01, 0.64)

HYPOKALAEMIA

Clodronate_1_Oral

2.36 (0.61, 9.12)

0.01

HYPOKALAEMIA

Zoledronic_acid_1_IV

1.35 (0.17, 10.92)

0.01

HYPOKALAEMIA

Zoledronic_acid_2_IV

0.91 (0.24, 3.43)

0.01

hyponatremia

Bisphosphonate

7.06 (0.36, 136.81)

2.94 (0.33, 3309.12)

0.0003

0 (0, 0.5)

Hypophosphatemia

Clodronate

0.34 (0.01, 8.24)

0.04 (0, 0.85)

0.0006

0 (0, 0)

Hypophosphatemia

Ibandronate

0.06 (0, 1.49)

0.0006

0 (0, 0)

Hypophosphatemia

Zoledronic_acid

0.07 (0, 1.58)

0.0006

0 (0, 0)

increased bone pain

Bisphosphonate

1.73 (1.47, 2.04)

1.79 (1.33, 2.49)

0.11

0.07 (0.03, 0.13)

INFECTION

Clodronate_Oral

1.13 (0.48, 2.66)

0.22

0.0009

INFECTION

Ibandronate_Oral

2.24 (1.18, 4.22)

0.22

0.0009

INFECTION

Zoledronic_acid_IV

1.02 (0.88, 1.19)

0.22

0.0009

Influenza-like symptoms

Bisphosphonate

22.18 (2.98, 164.89)

16.09 (2.04, 207.85)

0.03

0.33 (0.03, 0.85)

INR increased

Clodronate_1_Oral

0.09 (0.01, 1.65)

0.0030

INSOMNIA

Bisphosphonate

1.33 (0.59, 2.98)

1.26 (0.64, 2.81)

0.05

0.01 (-0.02, 0.07)

0.08

0.02 (-0.03, 0.12)

IRREGULAR MENSTRUATION

Bisphosphonate

1.08 (0.5, 2.36)

0.91 (0.31, 2.21)

0.02

0 (-0.02, 0.03)

ISCHAEMIC CARDIOVASCULAR DISEASE

Zoledronic_acid_IV

5.91 (0.24, 145.97)

3.52 (0.06, 776.16)

0.0030

0.01 (0, 0.72)

ISCHAEMIC CEREBROVASCULAR EVENT

Bisphosphonate

2.41 (0.68, 8.54)

1.55 (0.43, 6.91)

0.0020

0 (0, 0.01)

LEUCOCYTOPAENIA

Bisphosphonate

1.11 (0.66, 1.9)

0.99 (0.53, 1.99)

0.7

0 (-0.15, 0.12)

lipase increased

Non_nitrogenous

9.08 (0.49, 168.86)

12.1 (0.36, 85530.05)

0.0003

0 (0, 0.96)

LIVER PROBLEMS

Clodronate

0.91 (0.61, 1.37)

0.96 (0.48, 2.27)

0.08

0 (-0.04, 0.08)

LIVER PROBLEMS

Risedronate

5.2 (0.24, 113.59)

2.86 (0.19, 157.6)

0.08

0.12 (-0.06, 0.85)

LIVER PROBLEMS

Zoledronic_acid

0.15 (0.03, 0.83)

0.07 (0.01, 0.58)

0.08

-0.07 (-0.08, -0.03)

LOSS OF APPETITE

Bisphosphonate

1.36 (0.6, 3.11)

1.06 (0.43, 2.76)

0.0030

0 (0, 0.01)

LYMPHOEDEMA

Zoledronic_acid

0.97 (0.13, 7.27)

0.75 (0.16, 3.88)

0.27

-0.05 (-0.21, 0.32)

LYMPHOPAENIA

Bisphosphonate

0.49 (0.15, 1.66)

0.32 (0.05, 1.19)

0.01

-0.01 (-0.01, 0)

menometrorrhagia

Zoledronic_acid

2.51 (0.49, 12.97)

2.22 (0.24, 21.14)

MOTOR NEUROPATHY

Zoledronic_acid_2_IV

1.1 (0.68, 1.79)

0.18

MUCOSITIS

Bisphosphonate

0.76 (0.26, 2.25)

0.47 (0.09, 1.6)

0.03

-0.01 (-0.03, 0.02)

MUSCULOSKELETAL PAIN/EVENT

Bisphosphonate

1.33 (1.03, 1.71)

1.35 (0.9, 2.12)

0.11

0.03 (-0.01, 0.1)

0.0004

0 (0, 0)

Nasopharyngitis

Nitrogenous

0.89 (0.45, 1.75)

0.86 (0.43, 1.79)

0.08

-0.01 (-0.04, 0.05)

NAUSEA

Bisphosphonate

1.21 (1.08, 1.35)

1.33 (1.11, 1.63)

0.34

0.07 (0.02, 0.12)

0.05

0.02 (0.01, 0.03)

neuralgia

Nitrogenous

0.15 (0.03, 0.83)

0.23 (0.02, 6.16)

0.02

-0.01 (-0.02, 0.08)

neuralgia

Non_nitrogenous

4.03 (0.45, 36.14)

1.82 (0.03, 23.05)

0.02

0.01 (-0.02, 0.27)

NEUROSENSORY PROBLEMS

Bisphosphonate

1.23 (1.05, 1.45)

1.29 (1.05, 1.66)

0.1

0.03 (0, 0.06)

0.0000

0 (0, 0)

NEUTROPENIA

Bisphosphonate

0.95 (0.79, 1.15)

0.87 (0.49, 1.25)

0.04

0 (-0.02, 0.01)

neutrophil count decreased

Bisphosphonate

0.67 (0.49, 0.91)

0.6 (0.1, 1.12)

0.07

-0.03 (-0.06, 0.01)

OEDEMA

Nitrogenous

1.31 (0.87, 1.95)

1.33 (0.88, 2.13)

0.11

0.03 (-0.01, 0.1)

OEDEMA

Non_nitrogenous

1.14 (0.7, 1.98)

0.11

0.01 (-0.03, 0.08)

oesophagitis

Clodronate_Oral

5.04 (0.24, 105.07)

1.14 (0.18, 7.15)

0.01

0 (-0.01, 0.07)

oesophagitis

Ibandronate_Oral

2.46 (0.77, 7.9)

3.29 (0.84, 17.65)

0.01

0.03 (0, 0.17)

oesophagitis

Zoledronic_acid_IV

0.15 (0.03, 0.83)

0.19 (0.02, 1.28)

0.01

-0.01 (-0.01, 0)

ORAL MUCOSITIS

Nitrogenous

0.98 (0.85, 1.13)

0.96 (0.59, 1.61)

OsteoNecrosis of the Jaw

Nitrogenous

7.69 (2.31, 25.55)

0.0050

OTHER EYE DISORDERS

Clodronate_Oral

1.31 (0.25, 6.33)

0.03

0.01 (-0.03, 0.15)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Ibandronate_Oral

0.99 (0.42, 2.34)

0.82 (0.13, 4.71)

0.03

-0.01 (-0.03, 0.11)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Pamidronate_IV

0.65 (0.04, 8.83)

0.03

-0.01 (-0.03, 0.21)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Risedronate_Oral

0 (0, 0.55)

0.03

-0.03 (-0.03, -0.02)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Zoledronic_acid_IV

1.16 (0.85, 1.58)

1 (0.34, 2.46)

0.03

0 (-0.02, 0.05)

0.0000

0 (0, 0)

pain in extremity

Nitrogenous

2.29 (0.43, 12.16)

1.76 (0.49, 9.82)

0.14

0.08 (-0.07, 0.48)

0.05

0.04 (-0.03, 0.31)

pain in extremity

Non_nitrogenous

1.56 (0.41, 9.26)

0.14

0.06 (-0.08, 0.46)

0.05

0.03 (-0.03, 0.29)

PANCREATITIS

Nitrogenous

0.34 (0.01, 8.71)

0.08 (0, 1.25)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

PANCREATITIS

Non_nitrogenous

5.05 (0.59, 43.24)

1.46 (0.09, 12.17)

0.0006

0 (0, 0.01)

0.0004

0 (0, 0)

PARAESTHESIA

Nitrogenous

0.82 (0.31, 2.13)

0.57 (0.21, 1.83)

0.43

-0.13 (-0.29, 0.15)

periodontal disease

Zoledronic_acid_2_IV

15.34 (0.87, 269.36)

10.2 (1.14, 1322.28)

periodontal disease

Zoledronic_acid_2notai_IV

0.8 (0.21, 2.99)

0.82 (0.14, 4.39)

phlebitis

Bisphosphonate

1.07 (0.86, 1.33)

1.15 (0.56, 2.56)

PNEUMONIA

Bisphosphonate

1 (0.39, 2.54)

0.92 (0.21, 3.03)

0.0060

0 (0, 0.01)

PULMONARY EMBOLUS

Zoledronic_acid_1_IV

1.61 (0.77, 3.38)

0.02

renal impairment

Bisphosphonate

1.48 (0.7, 3.13)

1.56 (0.7, 3.55)

0.03

0.02 (-0.01, 0.07)

0.0004

0 (0, 0)

SKIN DISORDER

Bisphosphonate

1 (0.87, 1.14)

1.05 (0.84, 1.4)

0.05

0 (-0.01, 0.02)

STOMATITIS

Clodronate_1_Oral

1 (0.26, 2.69)

0.15

0 (-0.11, 0.17)

STOMATITIS

Pamidronate_2_Oral

1.11 (0.85, 1.44)

1.12 (0.71, 1.76)

0.15

0.02 (-0.04, 0.09)

STOMATITIS

Zoledronic_acid_1_IV

1.05 (0.88, 1.26)

0.99 (0.5, 1.45)

0.15

0 (-0.07, 0.06)

STOMATITIS

Zoledronic_acid_2_IV

0.33 (0.09, 0.89)

0.15

-0.1 (-0.14, -0.01)

SYNCOPE

Nitrogenous

3 (0.1, 90.96)

1.11 (0.13, 15.35)

0.0040

0 (0, 0.06)

SYNCOPE

Non_nitrogenous

1.21 (0.37, 3.97)

0.78 (0.15, 2.97)

0.0040

0 (0, 0.01)

THROMBOEMBOLIC EVENTS

Clodronate

7.27 (1.41, 33.44)

0.02

0.11 (0.01, 0.38)

0.0009

0.01 (0, 0.03)

THROMBOEMBOLIC EVENTS

Ibandronate

13.15 (2.36, 68.93)

0.02

0.19 (0.03, 0.56)

0.0009

0.01 (0, 0.06)

THROMBOEMBOLIC EVENTS

Zoledronic_acid

3.18 (1.34, 7.51)

2.79 (0.99, 7.42)

0.02

0.03 (0, 0.11)

0.0009

0 (0, 0.01)

THROMBOPAENIA

Bisphosphonate

0.41 (0.06, 2.79)

0.26 (0.03, 1.35)

0.04

-0.03 (-0.04, 0.01)

THYROID CANCER

Zoledronic_acid

3 (0.1, 90.96)

0.04 (0, 5.68)

0.09

-0.09 (-0.09, 0.27)

TRAUMATIC FRACTURES

Nitrogenous

0.95 (0.45, 1.99)

0.87 (0.38, 1.95)

0.0060

0 (0, 0.01)

uterine dilation/curettage

Nitrogenous

1.04 (0.6, 1.82)

0.99 (0.44, 1.95)

uterine polyp

Zoledronic_acid_2_IV

0.75 (0.26, 2.18)

0.09

uterine polyp

Zoledronic_acid_2notai_IV

1.15 (0.75, 1.76)

0.09

VAGINAL BLEEDING

Bisphosphonate

4.03 (0.45, 36.39)

3.31 (0.18, 97.23)

0.0020

0 (0, 0.16)

VAGINAL DISCHARGE

Bisphosphonate

0.43 (0.11, 1.72)

0.14 (0.02, 0.52)

0.06

-0.06 (-0.06, -0.03)

VOMITING

Nitrogenous

1.02 (0.89, 1.18)

1.13 (0.89, 1.88)

0.19

0.02 (-0.02, 0.12)

0.0004

0 (0, 0)

VOMITING

Non_nitrogenous

1.67 (1.18, 2.92)

0.19

0.09 (0.03, 0.22)

0.0004

0 (0, 0)

MOOD DISTRUBANCES

Nitrogenous

1.24 (0.27, 5.71)

0.88 (0.13, 4.65)

Table 2: Summary of results for every event using only studies with complete reporting

Treatment

Direct OR

NMA OR

Baseline risk (cancer)

Risk difference (cancer)

Baseline risk (healthy)

Risk difference (healthy)

MYALGIA

MYALGIA

Clodronate

1.83 (0.69, 3.65)

0.03

0.03 (-0.01, 0.08)

MYALGIA

Ibandronate

2.55 (0.93, 5.54)

0.03

0.05 (0, 0.13)

MYALGIA

Zoledronic_acid

3.3 (2.06, 5.28)

3.22 (1.65, 5.83)

0.03

0.07 (0.02, 0.14)

stiffness

Zoledronic_acid_IV

4.71 (0.22, 101.87)

3.52 (0.19, 1185.28)

0.02

0.04 (-0.01, 0.93)

OTHERS

ABDOMINAL PAIN

Nitrogenous

2.31 (0.71, 7.55)

2.09 (0.78, 7.33)

0.13

0.11 (-0.03, 0.39)

ABDOMINAL PAIN

Non_nitrogenous

2.24 (0.77, 8.28)

0.13

0.12 (-0.03, 0.42)

ALANINE AMINOTRANSFERASE

Nitrogenous

0.53 (0.12, 2.44)

0.76 (0.24, 2.07)

0.0090

0 (-0.01, 0.01)

0.0004

0 (0, 0)

ALANINE AMINOTRANSFERASE

Non_nitrogenous

2.17 (0.88, 5.33)

1.79 (0.62, 4.69)

0.0090

0.01 (0, 0.03)

0.0004

0 (0, 0)

ALKALINE PHOSPHATASE

Zoledronic_acid_1_IV

0.45 (0.09, 2.22)

0.15

0.0000

ALKALINE PHOSPHATASE

Zoledronic_acid_2_IV

0.26 (0.05, 1.33)

0.15

0.0000

ALOPECIA

Bisphosphonate

1.46 (0.87, 2.43)

1.31 (0.77, 2.27)

0.06

0.02 (-0.01, 0.07)

ANAEMIA

Bisphosphonate

1.48 (0.74, 2.95)

1.41 (0.67, 2.74)

0.01

0 (0, 0.02)

ARTHRALGIA

Nitrogenous

1.37 (1, 1.88)

1.34 (0.95, 1.94)

0.17

0.04 (-0.01, 0.11)

0.0000

0 (0, 0)

ARTHRALGIA

Non_nitrogenous

1.06 (0.71, 1.61)

0.17

0.01 (-0.04, 0.08)

0.0000

0 (0, 0)

arthropathy/arthritis

Clodronate

1.17 (0.34, 2.91)

0.11

0.02 (-0.07, 0.16)

0.09

0.01 (-0.06, 0.13)

arthropathy/arthritis

Ibandronate

1.21 (0.24, 3.46)

0.11

0.02 (-0.08, 0.19)

0.09

0.02 (-0.07, 0.16)

arthropathy/arthritis

Risedronate

0 (0, 0.04)

0.11

-0.11 (-0.11, -0.11)

0.09

-0.09 (-0.09, -0.09)

arthropathy/arthritis

Zoledronic_acid

1.6 (0.91, 2.81)

1.21 (0.44, 2.38)

0.11

0.02 (-0.06, 0.12)

0.09

0.02 (-0.05, 0.1)

ASPARTATE AMINOTRANSFERASE

Nitrogenous

0.32 (0.1, 1.01)

0.48 (0.2, 1.37)

0.02

-0.01 (-0.01, 0.01)

0.0004

0 (0, 0)

ASPARTATE AMINOTRANSFERASE

Non_nitrogenous

1.44 (0.55, 3.8)

1.13 (0.46, 3.07)

0.02

0 (-0.01, 0.04)

0.0004

0 (0, 0)

ASTHENIA

Risedronate_1_Oral

NA (NA, NA)

0.08

ASTHENIA

Zoledronic_acid_1_IV

0.84 (0.1, 7)

0.08

ASTHENIA

Zoledronic_acid_2_IV

0.66 (0.13, 3.35)

0.08

BACK PAIN

Nitrogenous

2.19 (0.78, 6.13)

2.46 (1, 6.6)

0.08

0.1 (0, 0.29)

0.1

0.11 (0, 0.32)

BACK PAIN

Non_nitrogenous

1.97 (0.77, 5.58)

0.08

0.07 (-0.02, 0.25)

0.1

0.08 (-0.02, 0.28)

BILIRUBIN

Bisphosphonate

0.15 (0.03, 0.83)

0.07 (0.01, 0.55)

0.08

-0.07 (-0.08, -0.03)

CARDIAC: CONGESTIVE HEART FAILURE

Zoledronic_acid

0.2 (0.01, 5.17)

0.06 (0.01, 1.24)

0.04

-0.03 (-0.04, 0.01)

CARDIAC EVENTS

Clodronate_1_Oral

5.22 (0.25, 109.67)

7.84 (1.27, 33.46)

0.03

0.15 (0.01, 0.45)

0.0020

0.01 (0, 0.05)

CARDIAC EVENTS

Ibandronate_3_Oral

12.18 (2.01, 59.73)

0.03

0.22 (0.03, 0.6)

0.0020

0.02 (0, 0.09)

CARDIAC EVENTS

Risedronate_1_Oral

0 (0, 6.6)

0.03

-0.03 (-0.03, 0.13)

0.0020

0 (0, 0.01)

CARDIAC EVENTS

Zoledronic_acid_1_IV

1.54 (0.63, 3.72)

1.51 (0.56, 3.99)

0.03

0.01 (-0.01, 0.07)

0.0020

0 (0, 0.01)

CARDIAC EVENTS

Zoledronic_acid_2_IV

3.75 (0.8, 17.66)

2.61 (0.89, 8.17)

0.03

0.04 (0, 0.16)

0.0020

0 (0, 0.01)

CARDIAC EVENTS

Zoledronic_acid_4_IV

2.49 (0.71, 9.4)

0.03

0.04 (-0.01, 0.18)

0.0020

0 (0, 0.01)

CATARACT

Bisphosphonate

0.84 (0.26, 2.75)

0.0040

CELLULITIS

Bisphosphonate

0.21 (0.01, 5.28)

0.02 (0, 0.71)

0.04

-0.04 (-0.04, -0.01)

CHEST PAIN

Bisphosphonate

4.71 (0.22, 101.87)

0.91 (0.05, 31.56)

0.01

0 (-0.01, 0.27)

CHILLS

Zoledronic_acid_1_IV

10.35 (0.56, 190.21)

0.02

CHILLS

Zoledronic_acid_2_IV

8.03 (0.94, 68.6)

0.02

COLITIS

Bisphosphonate

1.01 (0.06, 16.11)

0.22 (0, 3.07)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

constipation

Bisphosphonate

0.54 (0.22, 1.3)

0.54 (0.24, 1.38)

0.42

-0.14 (-0.27, 0.08)

COUGH

Nitrogenous

2.17 (0.47, 10.08)

1.62 (0.42, 6.74)

0.02

0.01 (-0.01, 0.09)

0.12

0.06 (-0.06, 0.36)

COUGH

Non_nitrogenous

1.51 (0.37, 6.62)

0.02

0.01 (-0.01, 0.08)

0.12

0.05 (-0.07, 0.35)

CPK increased

Clodronate_Oral

5.04 (0.24, 105.07)

4.95 (0.13, 5537.82)

0.0003

0 (0, 0.63)

DECREASED APPETITE

Bisphosphonate

4.65 (0.62, 34.85)

5.4 (0.55, 605.12)

0.04

0.13 (-0.02, 0.92)

DEHYDRATION

Bisphosphonate

1.18 (0.44, 3.15)

0.98 (0.27, 3.15)

0.0080

0 (-0.01, 0.02)

DEPRESSION

Clodronate_1_Oral

0.89 (0.31, 2.6)

0.02

0 (-0.01, 0.03)

0.1

-0.01 (-0.07, 0.13)

DEPRESSION

Ibandronate_3_Oral

0.9 (0.31, 2.67)

0.02

0 (-0.01, 0.03)

0.1

-0.01 (-0.07, 0.13)

DEPRESSION

Zoledronic_acid_1_IV

1.83 (0.44, 7.58)

1.07 (0.42, 3.05)

0.02

0 (-0.01, 0.03)

0.1

0.01 (-0.06, 0.16)

DEPRESSION

Zoledronic_acid_2_IV

0.86 (0.32, 2.34)

0.93 (0.4, 2.17)

0.02

0 (-0.01, 0.02)

0.1

-0.01 (-0.06, 0.1)

DEPRESSION

Zoledronic_acid_4_IV

1.38 (0.55, 3.51)

0.02

0.01 (-0.01, 0.04)

0.1

0.03 (-0.04, 0.19)

DIARRHOEA

Nitrogenous

1.53 (0.66, 3.56)

1.82 (0.96, 3.68)

0.11

0.07 (0, 0.2)

0.03

0.03 (0, 0.08)

DIARRHOEA

Non_nitrogenous

3.34 (1.18, 9.45)

2.91 (1.48, 5.94)

0.11

0.15 (0.04, 0.31)

0.03

0.06 (0.02, 0.14)

DIZZINESS

Nitrogenous

1.56 (0.61, 3.95)

1.23 (0.49, 3.39)

0.03

0.01 (-0.01, 0.06)

0.09

0.02 (-0.05, 0.16)

DIZZINESS

Non_nitrogenous

0.89 (0.26, 2.6)

0.03

0 (-0.02, 0.04)

0.09

-0.01 (-0.07, 0.12)

dry mouth

Bisphosphonate

0.55 (0.2, 1.52)

0.34 (0.07, 1.11)

0.04

-0.03 (-0.04, 0)

DYSGEUSIA

Bisphosphonate

7.04 (1.2, 41.3)

6.26 (0.95, 74.5)

0.0010

0.01 (0, 0.07)

DYSPEPSIA

Clodronate_Oral

0.67 (0.07, 5.45)

0.04

-0.01 (-0.04, 0.15)

DYSPEPSIA

Ibandronate_Oral

0.85 (0.09, 6.76)

0.04

-0.01 (-0.04, 0.18)

DYSPEPSIA

Risedronate_Oral

0.43 (0.03, 4.68)

0.04

-0.02 (-0.04, 0.13)

DYSPEPSIA

Zoledronic_acid_IV

0.48 (0.04, 5.46)

0.26 (0.03, 2.07)

0.04

-0.03 (-0.04, 0.04)

dysphagia

Bisphosphonate

0.5 (0.11, 2.3)

0.25 (0.05, 2.29)

0.08

-0.06 (-0.07, 0.08)

0.0000

0 (0, 0)

DYSPNOEA

Zoledronic_acid_2_IV

9.72 (0.51, 186.7)

0.02

0.0004

Elevated creatinine

Bisphosphonate

1.03 (0.38, 2.78)

1.51 (0.28, 6.52)

0.08

0.04 (-0.06, 0.29)

FATIGUE

Clodronate_1_Oral

1.16 (0.34, 3.14)

0.1

0.01 (-0.07, 0.16)

0.21

0.03 (-0.12, 0.24)

FATIGUE

Ibandronate_3_Oral

1.59 (0.48, 5.36)

0.1

0.05 (-0.05, 0.28)

0.21

0.09 (-0.1, 0.38)

FATIGUE

Ibandronate_4_IVAndOral

4 (0.45, 36.64)

0.1

0.21 (-0.05, 0.71)

0.21

0.3 (-0.1, 0.7)

FATIGUE

Risedronate_1_Oral

0.62 (0.09, 4.05)

0.1

-0.04 (-0.09, 0.21)

0.21

-0.07 (-0.18, 0.31)

FATIGUE

Zoledronic_acid_1_IV

1.94 (1.32, 2.84)

1.9 (0.96, 3.94)

0.1

0.08 (0, 0.21)

0.21

0.12 (-0.01, 0.3)

FATIGUE

Zoledronic_acid_2_IV

1.76 (1.14, 2.73)

2.38 (1.22, 5.15)

0.1

0.11 (0.02, 0.27)

0.21

0.18 (0.04, 0.37)

FATIGUE

Zoledronic_acid_4_IV

2.43 (0.98, 6.75)

0.1

0.12 (0, 0.33)

0.21

0.18 (0, 0.43)

FEBRILE NEUTROPENIA

Clodronate

1.77 (0.52, 6.04)

1.42 (0.27, 6.33)

0.0040

0 (0, 0.02)

FEBRILE NEUTROPENIA

Ibandronate

4.65 (0.54, 39.94)

0.0040

0.02 (0, 0.14)

FEBRILE NEUTROPENIA

Zoledronic_acid

0.27 (0.03, 2.51)

0.35 (0.04, 3.24)

0.0040

0 (0, 0.01)

FEVER

Clodronate_1_Oral

6.54 (1.84, 45.74)

0.01

0.06 (0.01, 0.36)

FEVER

Ibandronate_3_Oral

8.83 (2.48, 60.44)

0.01

0.09 (0.02, 0.42)

FEVER

Zoledronic_acid_1_IV

17.55 (4.24, 72.7)

27.03 (10.19, 179.58)

0.01

0.25 (0.1, 0.69)

FEVER

Zoledronic_acid_2_IV

34.76 (8.48, 142.55)

30.72 (11.84, 178.43)

0.01

0.27 (0.12, 0.68)

FEVER

Zoledronic_acid_4_IV

6.8 (2.23, 38.99)

0.01

0.07 (0.02, 0.32)

GGT increased

Clodronate_1_Oral

5.04 (0.24, 105.07)

5.86 (0.18, 164076396.26)

0.0003

0 (0, 1)

HAND-FOOT SYNDROME

Clodronate_1_Oral

3.02 (0.12, 74.25)

0.0080

HAND-FOOT SYNDROME

Zoledronic_acid_1_IV

0.91 (0.05, 17.05)

0.0080

HAND-FOOT SYNDROME

Zoledronic_acid_2_IV

2.08 (0.12, 36.73)

0.0080

HEADACHE

Clodronate_Oral

1.6 (0.47, 3.18)

0.24

0.1 (-0.11, 0.26)

HEADACHE

Ibandronate_Oral

1.89 (0.64, 4.17)

0.24

0.13 (-0.07, 0.33)

HEADACHE

Risedronate_Oral

1.11 (0.26, 4.09)

0.24

0.02 (-0.16, 0.32)

HEADACHE

Zoledronic_acid_IV

2.19 (1.36, 3.52)

2.29 (1.32, 3.93)

0.24

0.18 (0.05, 0.31)

HEPATOTOXICITY

Bisphosphonate

1.42 (0.98, 2.05)

1.31 (0.77, 2.06)

0.26

0.06 (-0.05, 0.16)

HOT FLUSHES

Bisphosphonate

0.91 (0.71, 1.18)

0.88 (0.66, 1.18)

0.24

-0.02 (-0.07, 0.03)

0.32

-0.03 (-0.08, 0.04)

HYPERGLYCAEMIA

Clodronate_1_Oral

0.62 (0.26, 1.49)

0.0100

HYPERGLYCAEMIA

Zoledronic_acid_2_IV

2.55 (0.99, 6.61)

0.0100

HYPERTENSION

Nitrogenous

0.84 (0.21, 3.28)

0.61 (0.15, 2.37)

0.02

-0.01 (-0.02, 0.02)

0.16

-0.06 (-0.13, 0.15)

HYPERTENSION

Non_nitrogenous

0.82 (0.19, 3.29)

0.02

0 (-0.01, 0.04)

0.16

-0.02 (-0.12, 0.22)

hypertonia/muscle spasms

Bisphosphonate

3.68 (1.12, 12.05)

3.57 (0.94, 22.24)

0.04

0.1 (0, 0.46)

hypoalbuminemia

Bisphosphonate

5.04 (0.24, 105.07)

3.12 (0.13, 163.97)

0.0003

0 (0, 0.05)

HYPOCALCEMIA

Bisphosphonate

1.6 (1.03, 2.51)

1.5 (0.76, 2.81)

0.04

0.02 (-0.01, 0.07)

HYPOKALAEMIA

Nitrogenous

1.55 (0.4, 6.09)

1.48 (0.49, 4.38)

0.01

0.01 (-0.01, 0.04)

HYPOKALAEMIA

Non_nitrogenous

2.36 (0.61, 9.12)

1.9 (0.63, 5.67)

0.01

0.01 (0, 0.05)

hyponatremia

Nitrogenous

3.19 (0.3, 238.79)

0.0003

0 (0, 0.07)

hyponatremia

Non_nitrogenous

7.06 (0.36, 136.81)

3.03 (0.3, 232.19)

0.0003

0 (0, 0.07)

Hypophosphatemia

Clodronate_1_Oral

0.34 (0.01, 8.24)

0.0006

increased bone pain

Bisphosphonate

1.84 (1.37, 2.48)

1.86 (1.15, 3.08)

0.11

0.08 (0.02, 0.17)

INFECTION

Bisphosphonate

1.36 (0.93, 1.99)

1.04 (0.23, 3.51)

0.22

0.01 (-0.16, 0.28)

0.0009

0 (0, 0)

Influenza-like symptoms

Bisphosphonate

7.36 (0.37, 147.29)

2.03 (0.09, 42.41)

0.03

0.03 (-0.03, 0.57)

INR increased

Clodronate_1_Oral

0.09 (0.01, 1.65)

0.0030

INSOMNIA

Clodronate_1_Oral

0.93 (0.35, 2.39)

0.05

0 (-0.03, 0.06)

0.08

-0.01 (-0.05, 0.1)

INSOMNIA

Ibandronate_3_Oral

0.87 (0.32, 2.29)

0.05

-0.01 (-0.03, 0.05)

0.08

-0.01 (-0.06, 0.09)

INSOMNIA

Risedronate_1_Oral

1.23 (0.03, 27.08)

0.05

0.01 (-0.05, 0.52)

0.08

0.02 (-0.08, 0.63)

INSOMNIA

Zoledronic_acid_1_IV

1.83 (0.44, 7.58)

1.13 (0.46, 2.71)

0.05

0.01 (-0.02, 0.07)

0.08

0.01 (-0.04, 0.12)

INSOMNIA

Zoledronic_acid_2_IV

1.12 (0.41, 3.05)

1.12 (0.47, 2.54)

0.05

0.01 (-0.02, 0.06)

0.08

0.01 (-0.04, 0.1)

INSOMNIA

Zoledronic_acid_4_IV

0.74 (0.29, 1.8)

0.05

-0.01 (-0.03, 0.03)

0.08

-0.02 (-0.06, 0.06)

IRREGULAR MENSTRUATION

Bisphosphonate

1.08 (0.5, 2.36)

0.92 (0.36, 2.19)

0.02

0 (-0.01, 0.03)

ISCHAEMIC CARDIOVASCULAR DISEASE

Zoledronic_acid

5.91 (0.24, 145.97)

3.71 (0.09, 1180.23)

0.0030

0.01 (0, 0.8)

ISCHAEMIC CEREBROVASCULAR EVENT

Bisphosphonate

2.41 (0.68, 8.54)

1.49 (0.4, 6.88)

0.0020

0 (0, 0.01)

LEUCOCYTOPAENIA

Clodronate

1.11 (0.66, 1.9)

1.01 (0.43, 2.03)

0.7

0 (-0.2, 0.13)

LEUCOCYTOPAENIA

Ibandronate

0.75 (0.21, 1.78)

0.7

-0.06 (-0.37, 0.11)

LEUCOCYTOPAENIA

Risedronate

0.12 (0, 2.39)

0.7

-0.48 (-0.69, 0.15)

LEUCOCYTOPAENIA

Zoledronic_acid

0.98 (0.24, 2.2)

0.7

0 (-0.34, 0.14)

lipase increased

Clodronate_Oral

9.08 (0.49, 168.86)

12.14 (0.45, 798708.37)

0.0003

0 (0, 1)

LIVER PROBLEMS

Zoledronic_acid_IV

0.15 (0.03, 0.83)

0.06 (0.01, 0.65)

0.08

-0.07 (-0.08, -0.03)

LOSS OF APPETITE

Bisphosphonate

0.8 (0.22, 3)

0.46 (0.06, 2.41)

0.0030

0 (0, 0)

LYMPHOEDEMA

Bisphosphonate

0.97 (0.13, 7.27)

0.7 (0.15, 3.99)

0.27

-0.06 (-0.22, 0.32)

LYMPHOPAENIA

Bisphosphonate

0.49 (0.15, 1.66)

0.32 (0.06, 1.16)

0.01

-0.01 (-0.01, 0)

MOTOR NEUROPATHY

Clodronate_1_Oral

0.67 (0.11, 4.02)

0.18

MOTOR NEUROPATHY

Zoledronic_acid_2_IV

1.1 (0.68, 1.79)

0.18

MUCOSITIS

Bisphosphonate

0.76 (0.26, 2.25)

0.46 (0.03, 1.73)

0.03

-0.01 (-0.03, 0.02)

MUSCULOSKELETAL PAIN/EVENT

Bisphosphonate

1.2 (0.79, 1.82)

1.26 (0.71, 2.77)

0.11

0.03 (-0.03, 0.15)

0.0004

0 (0, 0)

Nasopharyngitis

Zoledronic_acid_1_IV

0.48 (0.14, 1.72)

0.08

Nasopharyngitis

Zoledronic_acid_2_IV

1.33 (0.28, 6.38)

0.08

NAUSEA

Bisphosphonate

1.23 (0.87, 1.73)

1.31 (0.86, 2.14)

0.34

0.06 (-0.03, 0.18)

0.05

0.02 (-0.01, 0.06)

neuralgia

Clodronate_Oral

4.03 (0.45, 36.14)

1.96 (0.03, 21.2)

0.02

0.02 (-0.02, 0.25)

neuralgia

Zoledronic_acid_IV

0.15 (0.03, 0.83)

0.25 (0.02, 7.4)

0.02

-0.01 (-0.02, 0.1)

NEUROSENSORY PROBLEMS

Bisphosphonate

1.56 (1.1, 2.21)

1.49 (1, 2.23)

0.1

0.04 (0, 0.1)

0.0000

0 (0, 0)

NEUTROPENIA

Nitrogenous

2.04 (0.7, 5.93)

2.33 (1, 5.43)

0.04

0.05 (0, 0.15)

NEUTROPENIA

Non_nitrogenous

0.68 (0.46, 1)

0.68 (0.36, 1.3)

0.04

-0.01 (-0.03, 0.01)

neutrophil count decreased

Bisphosphonate

0.67 (0.49, 0.91)

0.62 (0.09, 1.18)

0.07

-0.02 (-0.06, 0.01)

OEDEMA

Nitrogenous

1.3 (0.8, 2.1)

1.27 (0.8, 2)

0.11

0.03 (-0.02, 0.09)

OEDEMA

Non_nitrogenous

1.09 (0.63, 1.85)

0.11

0.01 (-0.04, 0.07)

oesophagitis

Clodronate

5.04 (0.24, 105.07)

1.11 (0.11, 7.43)

0.01

0 (-0.01, 0.07)

oesophagitis

Ibandronate

2.46 (0.77, 7.9)

3.25 (0.77, 15.68)

0.01

0.03 (0, 0.15)

oesophagitis

Zoledronic_acid

0.15 (0.03, 0.83)

0.19 (0.02, 1.4)

0.01

-0.01 (-0.01, 0)

OsteoNecrosis of the Jaw

Zoledronic_acid_1_IV

11.71 (0.65, 212.64)

0.0050

OTHER EYE DISORDERS

Clodronate_Oral

0.22 (0.03, 10.62)

0.03

-0.03 (-0.03, 0.24)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Ibandronate_Oral

0.34 (0, 24.84)

0.03

-0.02 (-0.03, 0.44)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Risedronate_Oral

0 (0, 0.32)

0.03

-0.03 (-0.03, -0.02)

0.0000

0 (0, 0)

OTHER EYE DISORDERS

Zoledronic_acid_IV

1.12 (0.61, 2.06)

0.42 (0.1, 1.61)

0.03

-0.02 (-0.03, 0.02)

0.0000

0 (0, 0)

pain in extremity

Bisphosphonate

2.29 (0.43, 12.16)

1.53 (0.42, 9.74)

0.14

0.06 (-0.08, 0.48)

0.05

0.03 (-0.03, 0.3)

PANCREATITIS

Clodronate_Oral

5.05 (0.59, 43.24)

1.99 (0.26, 18.61)

0.0006

0 (0, 0.01)

0.0004

0 (0, 0.01)

PANCREATITIS

Ibandronate_Oral

0 (0, 0.14)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

PANCREATITIS

Zoledronic_acid_IV

0.39 (0, 6.52)

0.0006

0 (0, 0)

0.0004

0 (0, 0)

PARAESTHESIA

Zoledronic_acid_IV

1.02 (0.25, 4.1)

0.54 (0.14, 3.09)

0.43

-0.14 (-0.33, 0.27)

PNEUMONIA

Bisphosphonate

1 (0.39, 2.54)

0.88 (0.2, 2.7)

0.0060

0 (0, 0.01)

PULMONARY EMBOLUS

Zoledronic_acid_1_IV

2.69 (0.11, 67.11)

0.02

renal impairment

Bisphosphonate

2 (0.63, 6.31)

1.36 (0.34, 4.92)

0.03

0.01 (-0.02, 0.11)

0.0004

0 (0, 0)

SKIN DISORDER

Bisphosphonate

1.6 (1.03, 2.48)

1.48 (0.87, 2.44)

0.05

0.02 (-0.01, 0.06)

STOMATITIS

Zoledronic_acid_1_IV

0.62 (0.13, 2.99)

0.39 (0.09, 2.8)

0.15

-0.09 (-0.14, 0.18)

STOMATITIS

Zoledronic_acid_2_IV

0.23 (0.04, 1.2)

0.16 (0.03, 1.22)

0.15

-0.13 (-0.15, 0.03)

SYNCOPE

Nitrogenous

3 (0.1, 90.96)

1.13 (0.11, 15.9)

0.0040

0 (0, 0.06)

SYNCOPE

Non_nitrogenous

1.21 (0.37, 3.97)

0.78 (0.14, 3.31)

0.0040

0 (0, 0.01)

THROMBOEMBOLIC EVENTS

Clodronate

16.15 (0.86, 206.82)

0.02

0.22 (0, 0.78)

0.0009

0.01 (0, 0.15)

THROMBOEMBOLIC EVENTS

Ibandronate

33.15 (1.62, 474.44)

0.02

0.38 (0.01, 0.88)

0.0009

0.03 (0, 0.3)

THROMBOEMBOLIC EVENTS

Zoledronic_acid

7.97 (1.4, 45.55)

4.38 (0.53, 46.06)

0.02

0.06 (-0.01, 0.46)

0.0009

0 (0, 0.04)

THROMBOPAENIA

Zoledronic_acid_IV

0.29 (0.01, 7.28)

0.13 (0.01, 1.88)

0.04

-0.04 (-0.04, 0.04)

THYROID CANCER

Zoledronic_acid

3 (0.1, 90.96)

0.04 (0, 2.19)

0.09

-0.09 (-0.09, 0.09)

TRAUMATIC FRACTURES

Risedronate_1_Oral

NA (NA, NA)

0.0060

uterine polyp

Bisphosphonate

3 (0.1, 90.96)

1.57 (0.04, 123.96)

0.09

0.05 (-0.09, 0.83)

VAGINAL BLEEDING

Bisphosphonate

4.03 (0.45, 36.39)

3.24 (0.3, 339.48)

0.0020

0 (0, 0.4)

VAGINAL DISCHARGE

Zoledronic_acid

0.43 (0.11, 1.72)

0.14 (0.03, 0.54)

0.06

-0.05 (-0.06, -0.03)

VOMITING

Nitrogenous

4 (0.72, 22.09)

0.19

0.0004

Other things to include in the paper

  • Simple meta-analysis

Should it be odds ratio, not risk difference, until we’ve discussed baseline? Discuss heterogeneity in ORs vs RDs To illustrate this, just point to forest plot ORs for homogeneity. Can we discuss het in baselines when choosing a baseline. Question whether we should be discussing risk differences here at all - as we want to make the baselines transparent. Could mention baseilne het as a motivator for picking a constant baseline. Just needs quick summary using direct-only data to motivate.

Group symptoms by class as in NMA results? Show number of studies contributing to the result in the row label

The data extracted from the 59 trials that fulfilled our criteria is shown in Supplementary Data 1. What is this?

Table 1 shows the study chars. Where is this? Should include blinding, follow up, any other data extracted

Subset analysis done for direct as well as NMA? [ suggest no! ]

  • NMA

notAI - indicate in supp Table 1 - is this table in there?

Appendix plots in progress. Adding more transparent direct data and model comparison

  • AZURE

both risk ratio and risk difference?

point out which are sig in azure alone

Methods

  1. Talk through how we did FEVER

  2. Forest plots for selected odds ratios

Healthy women analysis